The long-term objective of the proposed research is to determine the primary structures of functional domains and factors that regulate expression two receptors on human leukocytes which bind immune complexes, Fc receptor II (FcRII) and Fc receptor III (FcRIII). The affinity of FcRII on monocytes for murine IgG1 is heterogenous. Previous studies have shown that a single base-change and the resulting amino acid substitution at residue 133 very likely accounts for the inability of FcRIIon monocytes from some individuals to recognize and bind murine IgG1. This finding provides the first clue to the location of the ligand-binding domain of FcRII. Studies outlined in this proposal are designed to further examine relationships between the primary structure and functional domains of FcRII. The hypotheses will be tested that amino acids surrounding residue 133 of human monocyte FcRII constitute the ligand-binding site of the receptor, and that monocyte and platelet FcRII differ with respect to the primary structures of their cytoplasmic domains. FcRIII is a glycoprotein which is expressed on the surfaces of neutrophils, macrophages and natural killer (NK) cells. FcRIII preferentially binds aggregated IgG and immune complexes, and is expressed as either a phosphatidylinositol-linked (neutrophils) or integral membrane protein (natural killer cells). These different forms of FcRIII are encoded for by two separate genes and are expressed in a cell-specific manner. Studies outlined in this proposal are designed to determine the molecular basis for an abnormality of FcRIII expression on neutrophils from a patient with systemic lupus erythematosus. The hypothesis will be tested that the gene which encodes neutrophil FcRIII is either abnormal or not expressed. The studies outlined in this proposal should yield new information concerning the structure and function of Fc receptors on human leukocytes that mediate phagocytosis and other responses of cells to encounters with immune complexes. Since phagocytosis is crucial for the normal removal of immune complexes from the circulation, information derived from these studies also should enhance our understanding of the pathogenesis of some rheumatic diseases.